(P 400) A LONG-TERM PHASE 4 STUDY TO EVALUATE THE RISK OF HEPATOTOXICITY ASSOCIATED WITH PEXIDARTINIB TREATMENT

Objective: Tenosynovial giant cell tumor (TGCT) is a rare, nonmalignant neoplasm of the synovium, bursae, or tendon sheaths driven by overexpression of colony-stimulating factor-1 (CSF-1). Pexidartinib is a CSF-1 receptor inhibitor approved in the United States, Taiwan, and Korea for adult patients with symptomatic TGCT associated with severe morbidity or functional limitations who are not candidates for surgery (or further treatment [e.g., local radiotherapy] in Taiwan). Pexidartinib is only available in the United States through a Risk Evaluation and Mitigation Strategy (REMS) Program, TURALIO® REMS (tREMS), due to the risk of serious and potentially fatal hepatotoxicity.

This study is being conducted to fulfill a US FDA post-marketing requirement to better understand the mechanism of cholestatic hepatotoxicity associated with pexidartinib. Results from this study are designed to identify patients with the highest risk of hepatotoxicity and provide evidence-based dose modifications and monitoring recommendations, respectively.

Methods: This prospective, multicenter, phase 4 non-interventional study (NCT04635111) is enrolling patients who experience unintended cholestatic liver toxicities while on treatment with pexidartinib. The purpose of the study is to better understand the mechanism behind these cholestatic hepatoxicities with exposure to the drug.

Patients will be enrolled into the study if they experienced a cholestatic hepatotoxicity event after receiving pexidartinib as part of normal medical practice. Identification of eligible patients will occur through the tREMS Program and/or through routine pharmacovigilance. Enrolled patients will be followed for 10-years to assess long-term outcomes of hepatotoxicity, including duration of the initial hepatotoxicity, interventional and imaging procedures, liver test results, hepatic failure, liver transplant, and death related to hepatic failure.

Eligible patients are ≥18 years of age with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery who experience ≥1 of the following liver test abnormalities, during or following pexidartinib exposure, that did not have a clear alternative cause: (1) aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 x upper limit of normal (ULN) with concurrent total bilirubin (TBIL) >2 x ULN; (2) isolated TBIL >2 x ULN (excluding patients with Gilbert’s syndrome); (3) isolated AST or ALT >10 x ULN; (4) alkaline phosphatase >2 x ULN with gamma-glutamyl transferase >2 x ULN.

This study will use Baseline demographic and clinical data already collected as part of the tREMs patient registry. Blood samples will be collected during the hepatotoxicity event, and yearly thereafter, to evaluate liver function, other relevant safety tests, peripheral immune cells, and for potential pharmacogenomic testing. An optional liver biopsy may be collected from enrolled patients for central laboratory analysis of macrophage and other immune cells (eg, T cell, B cell, NK cell) to investigate possible mechanisms of hepatotoxicity. Given the nature and descriptive aims of the study, formal hypothesis testing will not be performed. Target enrollment is 10-30 patients, with a minimum of 5 patients from the first, third, and fourth liver test abnormality categories.

Results: Not Applicable

Conclusion: Not Applicable